1. Field of the Invention
The present invention relates to a resin-immobilized amine derivative and a solid state synthesis method of xcex2-aminocarbonyl compound.
2. Description of the Related Art
For peptide synthesis, for example, solid state synthesis methods using resin carriers have been known conventionally. Such solid state synthesis methods are effective means for simultaneous synthesis of a group of numerous types of analogous compounds. It has been suggested that solid state synthesis methods are applicable to various chemical reactions.
Practically, however, reactions to which solid state reaction is applicable are limited, disadvantageously, compared with liquid phase reaction as the principal reaction for chemical synthesis.
In such circumstances of the related art concerning solid state synthesis methods, the inventors of the present application have investigated about the enhancement of the effectiveness of solid state synthesis methods by efficiently progressing the most essential and important reaction for generating carbonxe2x80x94carbon bond in organic synthesis in solid phase.
The inventors of the application have found a new method for iminoaldol-type addition reaction with a catalyst, using as the starting material an imine compound recovered from the reaction of an amine compound with aldehydes. Therefore, it has increasingly been an important problem to establish a solid state synthesis method capable of practically more enhancing the efficiency of the method.
It is therefore a purpose of the invention of the application to provide new technical means for realizing the iminoaldol-type addition reaction as described above by a solid state synthesis method; more specifically, it is a purpose of the invention to provide a method for synthesizing xcex2-aminocarbonyl compounds, comprising applying a solid state synthesis reaction.
So as to attain the foregoing objectives, the present application provides a resin-immobilized xcex2-aminocarbonyl compound represented by the following formula in a first aspect of the invention: 
wherein P represents the principal chain of a resin polymer; Q represents a substituted or unsubstituted hydrocarbon side chain or a substituted or unsubstituted hydrocarbon side chain with a heteroatom interposed therein; R, and R2 and R3 independently represent a substituted or unsubstituted hydrocarbon group or heterocyclic group; R1 represents xe2x80x94OR0, xe2x80x94SR0 or R0 (R0 represents a substituted or unsubstituted hydrocarbon group or heterocyclic group).
In a second aspect of the invention, the application provides a resin-immobilized xcex2-aminocarbonyl compound of the aforementioned formula where, the hydrocarbon side chain Q represents the following formula:
xe2x80x94Q1xe2x80x94Oxe2x80x94Q2xe2x80x94 (in formula, Q1 and Q2 independently represent a substituted or unsubstituted hydrocarbon chain such as arylene, alkylenearylene or arylenealkylene).
The application provides a method for producing a resin-immobilized xcex2-aminocarbonyl compound in a third aspect of the invention, comprising allowing a resin immobilized imine of the formula I: Pxe2x80x94Qxe2x80x94Nxe2x95x90CHxe2x80x94R to react with a silyl ether.
In a fourth aspect of the invention, the application provides a method for producting xcex2-aminocarbonyl compound represented by either one of the following formulas (A) 
(where Q0 represents a substituent which is the remaining part of the side chain Q after the xcex2-aminocarbonyl compound is separated from the resin) or (B) 
comprising the cleavage of the xcex2-aminocarbonyl from the resin of the resin-immobilized xcex2-aminocarbonyl compound.
In a fifth aspect of the invention, the application provides a method for producing a xcex2-aminocarbonyl compound, comprising treatment of the resin-immobilized xcex2-aminocarbonyl compound of above formula II with a Lewis acid.
The application provides a resin-immobilized xcex2-aminocarbonyl compound represented by the formula II according to the first and second aspects of the invention. These have never been know to enable the solid state synthesis method of xcex2-aminocarbonyl compounds.
In the resin-immobilized xcex2-aminocarbonyl compound of the formula II, as described above, P represents the principal chain of a resin polymer and Q represents a side chain to bind to the principal chain, wherein the resin polymer composing the principal chain includes any of addition polymers, condensed polymers and cross-linked polymers thereof but preferably includes addition polymers of alkenes with carbonxe2x80x94carbon double bond or cross-linked polymers thereof. The alkenes include aliphatic olefins and aliphatic dienes and also include, xcex1, xcex2-aliphatic unsaturated carboxylic acids or esters thereof, xcex1, xcex2-aliphatic unsaturated nitriles and aromatic alkenes such as styrene, xcex1-methylstyrene and divinylbenzene. The addition polymers thereof or partially cross-linked polymers thereof are preferable.
It is needless to say that various condensed polymers of polyester, epoxy resins, polyether and polyamide are also included.
In accordance with the invention, the side chain Q includes substituted or unsubstituted hydrocaron chains or substituted or unsubstituted hydrocarbon chains with heteroatoms such as oxygen atom or nitrogen atom interposed therein, wherein the hydrocarbon chains then include various hydrocarbon chains such as aliphatic, alicyclic, aromatic and aromatic aliphatic hydrocarbon chains and are for example alkylene chain represented by xe2x80x94(CH2)nxe2x80x94 and phenylenealkylene chain. Otherwise, the hydrocarbon chains can satisfactorily be hydrocarbon chains with heteroatoms interposed therein.
These side chains Q are satisfactorily formed together with the principal chain P and are also satisfactorily formed by graft polymerization after the principal chain P is formed.
As the side chain Q, for example, hydrocarbon chains derived from the resin-immobilized amine Pxe2x80x94Q1xe2x80x94Oxe2x80x94Q2xe2x80x94NH2 are provided in accordance with the invention, wherein Q1 and Q2 are arylene, alkylenearylene or arylenealkylene. Specifically, preferable examples of the hydrocarbon chains are hydrocarbon chains with Ph (pheylene chain), such as xe2x80x94Phxe2x80x94, xe2x80x94(CH2)nxe2x80x94Ph, xe2x80x94PHxe2x80x94(CH2)nxe2x80x94, xe2x80x94Phxe2x80x94(CH2)nxe2x80x94Phxe2x80x94, particularly oxyphenylene chains, such as xe2x80x94Phxe2x80x94Oxe2x80x94Phxe2x80x94, xe2x80x94Phxe2x80x94(CH2)nxe2x80x94Oxe2x80x94Phxe2x80x94, xe2x80x94Phxe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94Ph.
These hydrocarbons can satisfactorily have various substituents with no inhibition of the solid state synthesis reaction but with an activity to activate the reaction. The substituents include hydrocarbon groups such as alkyl group and aryl group, halogen atom, alkoxyl group, acyloxy group, alkoxycarbonyl group, nitro group, cyano group and heterocyclic group.
R, R2 and R3, and R0 composing R1 in the resin-immobilized xcex2-aminocarbonyl group of the formula II represent substituted or unsubstituted hydrocarbon groups or heterocyclic groups, wherein the hydrocabon groups include various linear or cyclic aliphatic or aromatic or aromatic aliphatic hydrocarbon groups, saturated or unsaturated. Similary, the heterocyclic groups include various heterocyclic groups containing oxygen or nitrogen. These are satisfactorily substituted with various substituents with no inhibition of the solid state synthesis reaction but with an activity to activate the reaction, for example hydrocarbon groups such as alkyl group and aryl group, halogen atom, alkoxyl group, acyloxy group, alkoxycarbonyl group, nitro group, cyano group and heterocyclic group.
In accordance with the invention, further, the resin-immoiblized amine of the formula III Pxe2x80x94Q1xe2x80x94Oxe2x80x94Q2xe2x80x94NH2 is provided as a substrate for the solid state synthesis of compounds containing nitrogen such as amino group. The resin-immobilized amine is essentially required for constructing a library of nitrogen-containing compounds for the solid state synthesis.
For example, xe2x80x94Q1xe2x80x94Oxe2x80x94Q2xe2x80x94 is more specifically described as such a structure as xe2x80x94Phxe2x80x94CH2xe2x80x94Oxe2x80x94Phxe2x80x94CH2xe2x80x94.
The reaction of various resin-immobilized amines including the resin-immobilized amine with aldehydes generates the resin-immobilized amine (imine?) of the formula I.
The resin-immobilized amine of the formula Pxe2x80x94Qxe2x80x94NH2 or Pxe2x80x94Q1xe2x80x94Oxe2x80x94Q2-NH2, as produced by aminating for example a resin polymer of a structure Pxe2x80x94QH and Pxe2x80x94QX (in the formula, X represents halogen atom) or reducing an amide of the formula Pxe2x80x94Q1xe2x80x94Oxe2x80x94Q2xe2x80x94CONH2 (in the formula, Q1 represents a part of the side chain Q), is allowed to react with aldehydes.
The resin-immobilized imine synthesis through the reaction with aldehydes is appropriately carried out in a solvent at a temperature of about xe2x88x9210 to 70xc2x0 C., preferably about 10 to 60xc2x0 C. The solvent appropriately includes DMF, DMSO, nitriles and halogenated hydrocarbons.
During the reaction, aldehydes are appropriately used at an equivalent weight ratio to the resin-immobilized imine within a range of 1 to 10 during the reaction.
The resin-immobilized imine represented by the formula I can be used as a substrate for solid-phase iminoaldol reaction. The reaction is carried out by allowing the resin-immobilized imine of the formula I to react with the silyl ethers.
The solid state reaction with the silyl ethers is progressed in a solvent, using for example a rare earth Lewis acid catalyst. As the solvent, for example, use can be made of halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, alcohols and water or appropriate mixture solvents thereof.
The rare earth Lewis acid satisfactorily includes rare earth metal compounds with Lewis acidity, for example organic acid ester salts, alcoholates, organic metal compounds and organic complex compounds of rare earth elements such as ytterbium (Yb), scandium (Sc), yttrium (Y), lanthanoid (La), samarium (Sm) and neodium (Nd). Among them, rare earth triflate for example Yb(OTf)3 is more appropriate.
The silyl ethers are used at an equivalent weight ratio of generally 0.5 to 10, preferably 1 to 7 to the resin-immobilized imine. The rare earth Lewis acid actalyst is used at an equivalent weight ratio of generally 0.01 to 1, preferably about 0.1 to 0.6.
The reaction temperature is appropriately xe2x88x9220 to 60xc2x0 C., more preferably ambient temperature or therearound.
In accordance with the invention, the resin-immobilized xcex2-aminocarbonyl compound can be recovered by the solid state reaction.
Together with the amine and imine, the resin-immobilized xcex2-aminocarbonyl compound serves as important means for constructing a library of various nitrogen-containing organic compounds.
By cleavage of the xcex2-aminocarbonyl compound from the immobilizing resin, the xcex2-aminocarbonyl compound of either one of the formulas A and B can be recovered.
As shown in the following examples, for example, the selectivity to the formula A or B depends on the conditions for the cleavage reaction.
Lewis acid is effectively used for the cleavage reaction. By using Lewis acid, the xcex2-aminocarbonyl compound can be detached under mild conditions in a smooth manner. Oxidative cleavage is also effective.
The invention will now be described in more detail in the following examples.